3-196654609-G-A

Variant names:

• chr3-196654609-G-A
• rs151257083
• NM_198565.3:c.70G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_198565.3(NRROS):​c.70G>A​(p.Gly24Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000715 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: NRROS NM_198565.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.74

Genes affected

NRROS (HGNC:24613): (negative regulator of reactive oxygen species) Enables transforming growth factor beta binding activity. Predicted to be involved in several processes, including microglia development; sequestering of TGFbeta in extracellular matrix; and transforming growth factor beta1 activation. Located in cell surface. [provided by Alliance of Genome Resources, Apr 2022]

PIGX (HGNC:26046): (phosphatidylinositol glycan anchor biosynthesis class X) This gene encodes a type I transmembrane protein in the endoplasmic reticulum (ER). The protein is an essential component of glycosylphosphatidylinositol-mannosyltransferase I, which transfers the first of the four mannoses in the GPI-anchor precursors during GPI-anchor biosynthesis. Studies in rat indicate that the protein is translated from a non-AUG translation initiation site. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018257618).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000604 (92/152306) while in subpopulation NFE AF= 0.00103 (70/68026). AF 95% confidence interval is 0.000835. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRROS	NM_198565.3	c.70G>A	p.Gly24Arg	missense_variant	Exon 2 of 3	ENST00000328557.5	NP_940967.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRROS	ENST00000328557.5	c.70G>A	p.Gly24Arg	missense_variant	Exon 2 of 3	1	NM_198565.3	ENSP00000328625.4
PIGX	ENST00000426755.5	c.-50G>A		5_prime_UTR_variant	Exon 2 of 6	3		ENSP00000409073.1
NRROS	ENST00000461791.1	n.202G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000458 AC: 115 AN: 251306 Hom.: 0 AF XY: 0.000464 AC XY: 63 AN XY: 135834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000739

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000727 AC: 1062 AN: 1461686 Hom.: 0 Cov.: 30 AF XY: 0.000682 AC XY: 496 AN XY: 727158

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000892

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74480

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000831 Hom.: 0

Bravo AF: 0.000612

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.000927

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.70G>A (p.G24R) alteration is located in exon 2 (coding exon 1) of the NRROS gene. This alteration results from a G to A substitution at nucleotide position 70, causing the glycine (G) at amino acid position 24 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Jun 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 24 of the NRROS protein (p.Gly24Arg). This variant is present in population databases (rs151257083, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NRROS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1423459). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NRROS protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Seizures, early-onset, with neurodegeneration and brain calcifications Uncertain:1

Aug 24, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.060
Sift	Benign	0.092	T
Sift4G	Benign	0.12	T
Polyphen		0.14	B
Vest4		0.20
MutPred		0.53		Gain of MoRF binding (P = 0.0049);
MVP		0.35
MPC		0.47
ClinPred		0.029	T
GERP RS		3.7
Varity_R		0.071
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs151257083; hg19: chr3-196381480;